PROJECT SUMMARY/ABSTRACT There is a pressing and unmet need for non-invasive biomarkers that permit identification of individuals at elevated risk of Alzheimer?s disease and related dementias before clinical disease manifestation and irreversible injury has occurred. Ideally, such markers might even identify unexpected therapeutic targets. Plasma proteomic profiles may provide a critical innovation to identify these individuals in a minimally invasive fashion. The overall objective of this proposal is to identify plasma proteomic profiles associated with future risk of dementia. This K01 Mentored Research Scientist Career Development Award entitled ?Proteomics profiling and risk of dementia? will leverage existing data from the Cardiovascular Health Study (CHS) and the Ginkgo Evaluation of Memory (GEM) Study, which conducted detailed prospective ascertainment of dementia in its population- based cohorts of elders. Proteomic profiles are currently measured using liquid chromatography?mass spectrometry in plasma samples of 3,602 CHS participants included in the prospective CHS Cognition Study and in plasma samples of 200 participants of the GEM study. Aim 1 assesses the associations of plasma proteins with risk of subsequent dementia among 3,602 dementia-free CHS participants (480 of whom subsequently developed dementia during an average of 5.4 years of follow-up). Aim 2 assesses the association of plasma protein networks with risk of subsequent dementia among the same CHS participants. Aim 3 externally validates the association of plasma proteins or protein clusters related to dementia in aim 1 or 2 with dementia risk in 100 dementia cases and 100 matched controls samples from the GEM study. These aims correspond to National Institute on Aging?s mission to ?support and conduct biological research on aging and to foster the development of research scientists on aging.? Findings from this project have a high likelihood of significant clinical impact, allowing targeted approaches to dementia prevention and intervention. This project will provide the applicant with exceptional mentorship and training in systems epidemiology, Alzheimer?s disease and related dementia, proteomics analysis and statistical inference using high- dimensional data from a dedicated group of faculty mentors including Dr. Kenneth J. Mukamal, MD, MPH, Majken K. Jensen, PhD, Steve DeKosky, MD, and Hanno Steen, PhD. In addition, several collaborators with complimentary areas of expertise will provide guidance and support. Dr. Koch will be fully equipped for a highly productive career as an independent investigator utilizing epidemiological expertise and high-dimensional data analysis to identify risk factors for dementia and its progression. Finally, with the advanced skills and knowledge that this award would provide, Dr. Koch will be ideally situated to apply for future NIH funding to identify and test novel risk modification strategies for dementia.